BLU-782 is an oral precision therapy specifically designed to selectively target mutant ALK2[1].
FOP is a rare genetic disorder characterized by the abnormal transformation of skeletal muscle, ligaments and tendons into bone, either spontaneously or as the result of physical trauma. FOP is caused by a mutation in the gene for ALK2, which is known as ACVR1, that causes hypersensitivity to certain bone morphogenetic proteins (BMP) and a neomorphic response to activins[4,5].
BLU-782 demonstrated exquisite selectivity for R206H mutant ALK2 in cellular assays, while sparing closely related anti-targets including ALK1, ALK3, and ALK6. Additionally, BLU-782 potently inhibited mutant ALK2 in vitro, regardless of the activating ligand, including Activin A, Activin B and BMP6. In vivo studies in a conditional knock-in ALK2R206H transgenic mouse model showed BLU-782 prevented the formation of injury-induced HO and edema, as measured by micro computed tomography and magnetic resonance imaging. Immunohistochemistry analyses also showed restoration of a healthy response to tissue injury in ALK2R206H mice, including skeletal myofiber regeneration. In addition, BLU-782 prevented the formation of surgery-induced HO following fibular osteotomy surgery in ALK2R206H mice[1]. BLU-782 dampens edema early and prevents HO in ALK2R206H mice[7].
The Phase I clinical trial BLU-782 in healthy volunteers to establish its safety of the investigational drug was recently completed (NCT03858075), and the result showed that BLU-782 is well tolerated with approximately 24 h of half-life and displays excellent properties of pharmacokinetics and pharmacodynamics[2,3].
Blu-782 selectively targets only mutant ALK2 with minimal interference to wild-type ALK2, which may be a good strategy for future FOP therapy[6].
References:
[1]: Blueprint medicines presents foundational preclinical data supporting the development of BLU-782, a highly selective ALK2 inhibitor, for the treatment of patients with fibrodysplasia ossificans progressive (2018)
[2]: Safety, tolerability, pharmacokinetics, and food effect of BLU-782 in healthy adults (2019). https://clinicaltrials.gov/ct2/show/NCT03858075. Accessed 14 Dec 2021
[3]: Alison DFA, Riadh L, Michael P, Cori AS, Sara G, Faith S, Sean K, Gordon W, Mark H, Robert S, Rachel S, Morgan L, Pauplis R, Vivek K, Andy B, Timothy L (2019) A clinical update on BLU-782, an investigational ALK2 inhibitor in development for fibrodysplasia ossificans progressiva (FOP). https://www.blueprintmedicines.com/wp-content/uploads/2019/09/Blueprint-Medicines-ASBMR-2019-BLU-782-Poster1.pdf.
[4]: Towler OW, Shore EM. BMP signaling and skeletal development in fibrodysplasia ossificans progressiva (FOP). Dev Dyn. 2022 Jan;251(1):164-177. doi: 10.1002/dvdy.387. Epub 2021 Jun 26. PMID: 34133058; PMCID: PMC9068236.
[5]: Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, Delai P, Fastnacht-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, K?ster B, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Morhart R, Mundlos S, Groppe J, Shore EM. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat. 2009 Mar;30(3):379-90. doi: 10.1002/humu.20868. PMID: 19085907; PMCID: PMC2921861.
[6]: Meng, X., Wang, H. & Hao, J. Recent progress in drug development for fibrodysplasia ossificans progressiva. Mol Cell Biochem 477, 2327-2334 (2022). https://doi.org/10.1007/s11010-022-04446-9
[7]: A clinical update on BLU-782, an investigational ALK2 inhibitor in development for fibrodysplasia ossificans progressiva (FOP)
BLU-782 是一种口服精准疗法，专门设计用于选择性靶向突变体 ALK2[1]。
FOP 是一种罕见的遗传性疾病，其特征是骨骼肌、韧带和肌腱异常转化为骨骼，这可能是自发的，也可能是身体外伤的结果。 FOP 是由 ALK2（称为 ACVR1）基因突变引起的，它会导致对某些骨形态发生蛋白 (BMP) 的超敏反应和对激活素的新形态反应[4,5]。
BLU-782 在细胞测定中表现出对 R206H 突变体 ALK2 的精妙选择性，同时保留了密切相关的抗靶标，包括 ALK1、ALK3 和 ALK6。此外，BLU-782 在体外有效抑制突变体 ALK2，无论激活配体如何，包括激活素 A、激活素 B 和 BMP6。条件性敲入 ALK2R206H 转基因小鼠模型的体内研究表明，通过微计算机断层扫描和磁共振成像测量，BLU-782 可防止损伤诱导的过氧化氢和水肿的形成。免疫组织化学分析还显示 ALK2R206H 小鼠恢复了对组织损伤的健康反应，包括骨骼肌纤维再生。此外，BLU-782 可防止 ALK2R206H 小鼠腓骨截骨手术后手术诱导的 HO 的形成[1]。 BLU-782 在 ALK2R206H 小鼠中早期抑制水肿并预防 HO[7]。
BLU-782 在健康志愿者中确定其研究药物安全性的 I 期临床试验最近完成 (NCT03858075)，结果表明 BLU-782 具有良好的耐受性，半衰期约为 24 小时，显示优异的药代动力学和药效学特性[2,3].
Blu-782 选择性地仅靶向突变体 ALK2，对野生型 ALK2 的干扰最小，这可能是未来 FOP 治疗的良好策略[6]。